title: A functional link between heme oxygenase-1 and tristetraprolin in the anti-inflammatory effects of nicotine.
abstract: Nicotine stimulates the cholinergic anti-inflammatory pathway and prevents excessive inflammation by inhibiting the release of inflammatory cytokines from macrophages. We have previously reported that heme oxygenase-1 (HO-1) and tristetraprolin (TTP) are induced by nicotine and mediate the anti-inflammatory function of nicotine in macrophages. However, it was not clear whether the two molecules are functionally linked. In this study, we sought to determine whether HO-1 associates with TTP to mediate the anti-inflammatory effects of nicotine. Inhibition of HO-1 activity or HO-1 expression attenuated the effects of nicotine on STAT3 activation, TTP induction, and TNF-α production in LPS-treated macrophages. Induction of HO-1 expression increased the level of TTP in the absence of nicotine. In an LPS-induced endotoxemia model, HO-1 deficiency blocked the effects of nicotine on the STAT3 phosphorylation, TTP induction, and LPS-induced TNF-α production in the liver. Downregulation of STAT3 by siRNA attenuated the effect of nicotine on TTP expression and TNF-α production but did not affect the nicotine-mediated induction of HO-1. In TTP knockout mice, nicotine treatment enhanced HO-1 expression and STAT3 activation but failed to inhibit LPS-induced TNF-α production. Our results suggest that HO-1 and TTP are functionally linked in mediating the anti-inflammatory effects of nicotine; HO-1 is necessary for the induction of TTP by nicotine. This novel nicotine-HO-1-TTP signaling pathway provides new possibilities for the treatment of inflammatory diseases.
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Md
authors.initials: M
authors.lastname: Jamal Uddin
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009538:Nicotine / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051816:Tristetraprolin / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D009538:Nicotine; D051547:Heme Oxygenase-1
keywords: Anti-inflammatory effects; CoPP; ECL; Free radicals; HO-1; KO; LPS; Nicotine; STAT3; SnPP; TNF; TTP; ZnPP; cobalt protoporphyrin; enhanced chemiluminescence; heme oxygenase-1; knockout; lipopolysaccharide; signal transducer and activator of transcription 3; tin protoporphyrin; tristetraprolin; tumor necrosis factor; zinc protoporphyrin